Introduction
Fungal infections of the nail, referred to by the terms “nail fungus,” “onychomycosis,” or “tinea unguium,” are common throughout the world. An estimated 2-13% of the population is affected in North America, with at least 15-20% of those aged 40-60 having one or more fingernails or toenails infected. Toenails are much more commonly affected than fingernails. Infections can range from superficial, causing little more than discoloration, to severe, resulting in loss of the nail together with deformities of the surrounding digit. The incidence of onychomycosis has been rising over the past few decades, due to factors such as an increased elderly population, increased participation in vigorous physical activity while wearing moisture-retaining shoes and socks, an increase in the number of HIV infected individuals, an increased incidence of diabetes, and increased use of steroids, antibiotics, and other therapeutics that can suppress immunologic responses to fungi.
While nail fungus is rarely life threatening, it causes significant pain, inconvenience, embarrassment, emotional distress, and limitations to manual performance and ambulation. Individuals with moderate to severe onychomycosis can lose their ability to perform many routine tasks (such as fastening buttons, picking up small objects, walking significant distances) and can lose the ability to perform satisfactorily in their occupations. Due to the unpleasant appearance of their hands or feet, these individuals may become socially self-conscious and embarrassed, and may avoid intimate or other close contact with people. Loss of self-esteem, anxiety, and depression commonly result from moderate to severe cases of fungal nail infection.
At present, topical treatments for nail fungus are rarely effective. Although some oral antifungal therapies have moderate efficacy, they also pose significant risks of toxic reactions, and many patients would prefer local, topical treatments to systemic treatments.
Etiology and Varieties
Onychomycosis is caused most commonly by several species of dermatophytes (parasitic fungi that infect the keratin-rich tissue of the stratum corneum, hair, and nails) and, less commonly, by nondermatophyte molds or by yeasts, primarily of the genus Candida. An estimated 90% of cases are caused by dermatophytes, primarily of the genera Trichophyton, Microsporum, and Epidermophyton, while about 8% are caused by nondermatophyte molds and 2% by yeasts. The causative agent in onychomycosis can rarely be determined by clinical appearance; microscopic examination or culturing is usually required. Furthermore, an infected nail colonized by one species can develop secondary infections by other fungi, yeasts, or bacteria.
Onychomycosis can affect the nail plate, the nail bed (the tissue directly under the nail plate), the nail matrix or nail root (the thickened skin at the base of the nail from which the nail plate develops), the cuticle, the hyponychium (the thickened layer of epidermis beneath the free end of the nail), and the proximal and lateral nail folds (the skin adjacent to the base and sides of the nail).
Factors that contribute to the development of onychomycosis include advanced age, diabetes (which reduces circulation to the extremities), wearing heat- and moisture-retaining footwear, communal bathing, HIV infection, the use of antibiotics or immunosuppressive drugs, trauma to the nail, use of insufficiently cleaned manicure tools, poor overall health, and warm climates.
Onychomycosis can be categorized into several varieties based on clinical appearance. The recognized varieties include:
Distal and lateral subungual onychomycosis (DLSO): This is the most common variety. It usually results from a fungal infection of the skin (usually the plantar skin of the foot) spreading to the nail bed and then to the underside of the nail plate via the hyponychium. The distal and lateral parts of the nail plate become thickened, white, and opaque. In addition, the nail bed becomes hyperkeratotic and onycholysis (separation of the nail plate from the bed, ultimately resulting in loss of the nail) commonly ensues. Paronychia (inflammation of the tissues adjacent to the nail) is also common. Trichophyton rubrum is the most common pathogen.
Endonyx onychomycosis (EO): This is a variety of DLSO in which the fungus spreads directly from the skin to the nail plate rather than to the nail bed. The nail again is thickened, white, and opaque, but there is no evident nail bed hyperkeratosis or onycholysis.
White superficial onychomycosis (WSO): This variety is almost always found on toenails. The surface of an infected nail develops white dots or powdery patches and the nail becomes rough and crumbly. Trichophyton mentagrophytes (T. interdigitale) is the most common cause, though some nondermatophyte molds such as Acremonium, Aspergillus, and Fusarium can also infect the upper surface of the nail plate. The nondermatophyte molds commonly cause black or green nails.
Proximal subungual onychomycosis (PSO): In this least common variety, the fungus first attacks the cuticle and proximal nail fold, and then penetrates the proximal nail plate. The distal part of the nail remains normal.
Candida Onychomycosis (CO): The yeast, nearly always Candida albicans, infects the nail folds (paronychia), the nail plate and surrounding tissues (in chronic mucocutaneous candidiasis), the nail bed, or any combination of these. The entire digit commonly becomes swollen and deformed. Candida may cause onycholysis or it may colonize onycholytic nails (resulting from trauma or another infection). Candida infection associated with paronychia is almost always secondary to trauma to the nail folds.
Total dystrophic onychomycosis (TDO): The entire nail plate is thickened, yellow-brown, and opaque. All the adjacent tissues are affected, and the nail matrix may be permanently damaged, preventing normal nail growth even after the infection resolves. TDO can be the endpoint of any of the other onychomycosis varieties.
A patient with onychomycosis may have one variety or any combination of varieties.
Current Treatments
Onychomycosis is presently treated primarily with oral antifungal agents. Topical agents are rarely effective by themselves, except in mild cases that only affect the distal nail plate. They may, however, be beneficial in combination with oral therapy. In severe cases, the affected nail (and sometimes the nail bed and matrix) is removed surgically or by use of a urea containing formulation; removal of the nail is done in conjunction with oral and sometimes topical therapy. Further details on some of these methods follow.
Oral medications: The preferred therapy for onychomycosis is orally administered treatment with terbinafine (Lamisil™), itraconazole (Sporanox™), or fluconazole (Diflucan™). Terbinafine, an allylamine, is active against dermatophytes, but has considerably less efficacy against nondermatophyte molds and against yeasts. Itraconazole and fluconazole are triazoles that are effective against dermatophytes, nondermatophyte molds, and yeasts. When administered daily, all of these compounds can cause hepatic injury, and monitoring of liver enzymes is required. Pulse therapy (typically, administration one week per month) reduces the risks for hepatic damage, but prolongs the course of therapy from about 6 to 12 weeks to at least several months. Terbinafine has several potentially serious drug interactions, and the triazoles, because they are metabolized using the hepatic cytochrome P450 system, have numerous significant drug and food interactions that prevent their use in many patients. Even though these drugs are the currently preferred treatments for onychomycosis, their cure rates are not high: a recent survey (Arch Dermatol 134(12):1551-1554, 1998) found that standard treatment with terbinafine resulted in disease-free nails in approximately 35-50% of cases, while the rate for itraconazole was approximately 25-40%. Relapse is also common, though precise figures are not available. These oral therapies are nevertheless more effective than topical treatments because they apparently penetrate the nail more quickly and thoroughly, and because they remain in the nail for weeks or months following treatment.
Topical treatments: Topical antifungal treatments are now administered mainly in cases where the fungal infection is restricted to the distal half of the nail plate or in cases in which the patient cannot tolerate oral therapy. Again, their low efficacies appear due mainly to their inability to adequately penetrate the nail. Topical antifungal agents include allylamines (including terbinafine), triazoles (including itraconazole and fluconazole), imidazole derivatives (including ketoconazole, miconazole, clotrimazole, and enconazole), amorolfine, ciclopirox olamine, sodium pyrithione, bifonazole plus urea, and propylene glycol plus urea plus lactic acid.
Existing treatments for onychomycosis are thus of limited efficacy, have high risks for adverse effects and drug interactions, and are time consuming and inconvenient for the patient. Furthermore, (based on conversations with practicing dermatologists) a large majority of onychomycosis patients would prefer a local, topical treatment to a systemic treatment that carries a significant risk of adverse effects. It has now been discovered that certain basic compositions, when used as described herein to enhance the permeation of antifungal compounds into the nail and surrounding tissues, successfully treat nail fungus locally, with much higher efficacy than for other topical treatments. The present invention provides a novel treatment for nail fungus that is effective, safe, not painful, and convenient.